Levosimendan, which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and the method for its preparation is described in EP 565546 B1. Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin. Levosimendan is represented by the formula: 
The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066 and in Lilleberg, J. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S63-S69, 1995. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E.-P. et al., J. Cardiovasc. Pharmacol., 26(Suppl.1), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients.
The electrical signal that initiates each normal heart beat arises from a small structure located at the top of right atrium. The structure is called “sinus node” or “sinoatrial node”. The sinus node is the natural pacemaker of the heart. It initiates the cardiac cycle of systole and diastole phases by generating an electrical impulse that spreads over the right and left atria, causing them to contract almost simultaneously. This electrical impulse is generated by the depolarization of the myocardial cells of the sinus node. The atria are electrically insulated from the ventricles by the atrioventricular (AV) groove. There is one area of the heart where the atria and the ventricles are electrically connected. This connection which actually comprises the second electrical structure of the heart is called the atrioventricular node or AV node. All electrical signals from the atrium must pass through the AV node in order to get to the ventricles. The impulse then continues from the AV node through the bundle of special cells designed to rapidly conduct the electrical signal through the ventricles. These fibers eventually branch out to the distant ventricular tissues. Stimulation of these fibers causes the ventricles to contract almost simultaneously and discharge of blood into the circulatory systems.
Various dysfunctions of the heart lead to altered beating. One such dysfunction is sick sinus syndrome (SSS), a progressive sinus node dysfunction often with further involvement of sinoatrial conduction disorders. Its diagnostic criteria include (i) inappropriate sinus rate-bradycardia for the underlying physiologic state (chronotropic incompetence), (ii) significant sinus pauses (<3 seconds) or arrest, (iii) sinoatrial exit block not related to drug therapy, (iv) chronic atrial fibrillation with an unacceptably slow ventricular response, (v) tachycardia-bradycardia syndrome, (vi) prolonged corrected sinus node recovery time and (vii) prolonged sinus node refractoriness and sinoatrial conduction time (Alagona, MD, Current Opinion in Cardiology, 1997, 12:3-11).
SSS with severe slowing of the heart beat (bradycardia) is associated with significant symptoms such as fatigue and shortness of breath. Sometimes the sinus node stops firing temporarily, and long pauses in the heart rhythm may result. The causes of sick sinus syndrome are usually intrinsic such as aging, sinoatrial nodal artery disease, scarring, or physical damages. There can also be extrinsic sinus node problems due to medications, hormonal conditions (such as an underactive thyroid gland) or neurological imbalances.
At the moment, there is no successful medical treatment for sick sinus syndrome. It is usually treated with a permanent pacemaker, a small electronic device implanted in the body of the patient. Thus, there is a strong need for a drug that would be effective in the treatment of sick sinus syndrome.